This is a competing renewal application for a unique case-control study of childhood Hodgkin's disease (HD) that includes epidemiologic, virologic, and genetic components. Cases of this extremely rare childhood cancer are obtained from the Children's Cancer Group and the Pediatric Oncology Group. Controls are selected by random digit dialing and individually matched to cases on age, sex, and race. Epidemiologic data on cases and controls are collected by telephone interviews of the parents. The previous grant, for an interview study of 300 HD cases and 484 controls, was focused on environmental risk factors, particularly exposures to infectious diseases. The new grant will allow us to expand data collection to a total 415 cases and 675 controls, to extend the family aggregation studies, to collect tumor specimens and blood samples from all 415 cases for virologic assays, and to create a biologic specimen bank. The major focus of the new study is still on the risk of HD in relation to early childhood infectious diseases. Approximately 36% of childhood cases from a pilot study of our subjects have been found to have the Epstein-Barr virus (EBV) in their tumor tissues. Thus, attention will be directed to the role of EBV through molecular biologic studies of HD tumor tissue and limited EBV serologic studies. Section from formalin- fixed, paraffin-embedded blocks of HD tumor tissue will be studied by polymerase chain reaction (PCR), in situ hybridization, and immunoperoxidase antigen detection. This proposed study, therefore, has the potential of providing the first comprehensive information on the relationship between EBV and HD by linking viral identification techniques to epidemiologic data gathered from the interview questionnaires. Preliminary analyses of our data suggest that cases are two times more likely than controls to have a first-degree relative with HD and other cancers (OR=2.21, 95%CI=1.03-4.75). Since subjects' families are young, further data on the occurrence of cancer in families of the cases and controls from the initial study will be collected by a follow-up interview in the year 03. In the new study, complex segregation analyses will be done to assess patterns of inheritance. Preliminary segregation analyses of the family data suggest that the model that best fits our observations is that of familial aggregation due to environmental factors rather than to Mendelian inheritance. Other risk factors to be evaluated in the study include breast feeding, socioeconomic status, parents' use of recreational drugs during pregnancy, childhood environmental exposures, and parents' occupational and environmental exposures. A repository of plasma and white blood cell samples from cases, and of sections of their Hodgkin's disease tumor tissue, will be established and maintained for future investigation. In summary, we believe that this multidisciplinary approach can provide breakthroughs in our understanding of childhood Hodgkin's disease by addressing the interaction of environmental, virologic, and genetic risk factors in the causation of childhood cancer.